Voltage-dependent gating of NR1/2B NMDA receptors.
Ligand-gated ion channels are activated by agonist binding, but may also be modulated by membrane voltage. N-Methyl-d-aspartate receptors (NMDARs) exhibit especially strong voltage dependence due to channel block by external Mg(2+) (Mg(o)(2+)). Here we demonstrate that activity of NMDARs composed of NR1 and NR2B subunits (NR1/2B receptors) is enhanced by depolarization even in 0 Mg(o)(2+), causing slow current relaxations in response to rapid voltage changes. We present a kinetic model of receptor activation that incorporates voltage-dependent gating-associated NR2B subunit conformational changes. The model accurately reproduces current relaxations during depolarizations and subsequent repolarizations in 0 Mg(o)(2+). Model simulations in physiological Mg(o)(2+) concentrations show that voltage-dependent receptor gating also underlies the slow component of Mg(o)(2+) unblock, a phenomenon that previously was shown to influence Mg(o)(2+) unblock kinetics during dendritic spikes. We propose that voltage-dependent gating of NR1/2B receptors confers enhanced voltage and time dependence on NMDAR-mediated signalling.
Clarke
Richard J
RJ
Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Johnson
Jon W
JW
D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D011487:Protein Conformation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000502:physiology*; D014162:Transfection
C409466:NR1 NMDA receptor; C473649:NR1A NMDA receptor, rat; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C464436:NR2D NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D008274:Magnesium